Is LCA5 p.Pro216Arg (c.647C>G) pathogenic?

LCA5 p.Pro216Arg (c.647C>G) is classified Conflicting classifications of pathogenicity in LCA5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-01-09). AlphaMissense: likely pathogenic (0.7194); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LCA5 p.Pro216Arg (c.647C>G)?

LCA5 p.Pro216Arg (c.647C>G) is associated with Inborn genetic diseases (ClinVar).

How common is LCA5 p.Pro216Arg (c.647C>G) in the general population?

LCA5 p.Pro216Arg (c.647C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about LCA5 p.Pro216Arg (c.647C>G)?

AlphaMissense predicts likely pathogenic (score 0.7194) — an in-silico prediction, not a clinical call.

LCA5 p.Pro216Arg

c.647C>G · rs1766296436 · VCV865776

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7194 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7194	likely pathogenic · top 8% in LCA5
REVEL	0.272	benign-leaning
SaProt	LLR -7.90	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 32 kb · p 0.58 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,756 alleles

Overall 6.2e-05% 1/1,613,496 alleles · very rare exomes 1/1,461,592 · genomes 0/151,904 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: LCA5
Protein: p.Pro216Arg
Coding: c.647C>G
MANE Select: NM_001122769
dbSNP: rs1766296436
Type: single nucleotide variant
Location: chr6:79513285 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.05

Full LCA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LCA5 p.Ala107Thr Uncertain significance ★★ ⚠ same condition
LCA5 p.Ala425Pro Uncertain significance ★★ ⚠ same condition
LCA5 p.Ala683Pro Uncertain significance ★★ ⚠ same condition
LCA5 p.Arg163His Uncertain significance ★★ ⚠ same condition
LCA5 p.Arg174His Uncertain significance ★★ ⚠ same condition
LCA5 p.Arg183Gln Uncertain significance ★★ ⚠ same condition
LCA5 p.Arg213Gly Uncertain significance ★★ ⚠ same condition
LCA5 p.Arg375Ser Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/lca5-p-pro216arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown